Modeling the Relationships Between Molecular Structure and Inhibition of Virus-Induced Cytophatic Effects: Anti-Hiv-1 and Anti-H1n1 (Influenza A) Activities as Examples

Abstract

In this paper we tested the hypothesis that the building up of model-based methods to correlate molecular structure with the concentration required for the production of some biological effects such as giant cell formation, reduction of the number of viable cells, etc. is possible. We provide data supporting this model presenting structure-relationships results for two sets of molecules displaying inhibitory activity against some effects of HIV-1 and H1N1 viruses. The local atomic reactivity indices were calculated at the ZINDO/1 level of the theory. We found several statistically significant equations showing that some process is charge-, orbital-and/or steric-controlled. The main and most important conclusion is that the method, originally designed only for in vitro molecule-site equilibrium constants, nicely works for other properties like cytopathicity protection and cytostatic concentrations. This opens an entirely new research field and raises the possibility that this methodology be applied to other types of reports of biological activity data. We conjecture that this method is superior to the Hansch approach and that it is related in a still unknown form to the Hammett methodology.

Quantum-chemical Modeling of the Relationships between Molecular Structure and In Vitro Multi-Step, Multimechanistic Drug Effects. HIV-1 Replication Inhibition and Inhibition of Cell Proliferation as Examples

“…In the first one, good results were obtained for the relationship between accumulation capacity and molecular structure in a group of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls in some zucchini subspecies [13]. In a more recent study, we obtained good quality results concerning structure-biological activity relationships for two different sets of molecules presenting inhibitory activity against some effects of HIV-1 (inhibition of HIV-induced cytopathicity and cytostatic effects) and H1N1 virus (decrease of H1N1-induced cytopathic effects) [14]. These results are encouraging and seem to suggest that the approach used here is appropriate.…”

“…During the last three decades we have developed a formal method [1] to correlate in vitro receptor binding affinity constants with the electronic structure and substituent orientational parameters of drug molecules [2][3][4][5][6][7][8][9][10][11][12][13][14][15][16]. A formal or non-empirical method is based on the following philosophy: it begins by proposing a model to explain a given biological activity.…”

Quantum Chemical Study of the Relationships Between Electronic Structure and Pharmacokinetic Profile, Inhibitory Strength Toward Hepatitis C Virus Ns5b Polymerase and HCV Replicons of Indole-Based Compounds

“…In the first one, interesting results were obtained for the relationship between accumulation capacity and molecular structure in a group of polychlorinated dibenzo-p-dioxins, polychlorinated dibenzofurans and polychlorinated biphenyls in some zucchini subspecies 76 . In the second one we obtained good quality results concerning structure-biological activity relationships for two different sets of molecules presenting inhibitory activity against some effects of HIV-1 (inhibition of HIV-induced cytopathicity and cytostatic effects) and H1N1 virus (decrease of H1N1-induced cytopathic effects) 77 . In the third one we found relevant structure-activity relationships for the inhibition of HIV-1 WT replication by some phenylaminopyridine derivatives and the inhibition of cell growth by several 1-azabenzanthrone derivatives 75 .…”

“…This choice is right because after geometry optimization this is the only method producing positive nucleophilic superdelocalizabilities as required by the model. Its application gave good results when applied to drug-receptor interaction studies 62 and biological activities (inhibition of wild-type and drug-resistant HTV-1 reverse transcriptase 63 , accumulation of polychlorinated molecules 76 and inhibitory activity against some effects of HIV-1 and H1N1 viruses 77 ). It is worth mentioning that, in general but not always, semiempirical methods give better QSAR results that Hartree-Fock or Density Functional ones 65,81 .…”

A Theoretical Study of the Relationships between Electronic Structure and CB1 and CB2 Cannabinoid Receptor Binding Affinity in a Group of 1-Aryl-5-(1-H-pyrrol-1-yl)-1-H-pyrazole-3-carboxamides

“…For the sake of clarity we present in Table 1 a summary of these local atomic reactivity indices (LARIs) together with their physical meaning. Some of these new indices have appeared in recent QSAR studies [56,62].…”